Pharmaceutical compositions having β-adrenoceptor antagonist activity employing pyridazinone derivatives

ABSTRACT

This invention relates to (isopropyl and tertiary butyl-amino-2-hydroxypropoxy)phenyl-3[2H]-pyridazinones which have β-adrenoceptor antagonist activity.

This is a continuation of application Ser. No. 642,979, filed Aug. 21,1984 now abandoned.

The present invention relates to pharmaceutical compositions containingpyridazinone derivatives for use as β-adrenoceptor antagonists, and inparticular to such compositions wherein the pyridazinone is substitutedby a phenyl group substituted by a β-blocking side chain. This inventionalso relates to methods of producing β-adrenoceptor antagonist activitywith these pyridazinone derivatives and to certain novel compounds whichmay be used in the compositions and methods of this invention.

Pyridazinones substituted in the 6-position by a phenyl group having aβ-blocking side-chain are generically known from U.S. Pat. No.4,053,601. However they are described therein as intermediates in thepreparation of hydrazine derivatives which are stated to haveβ-adrenoceptor antagonist and vasodilator activity. There is nosuggestion that the intermediates would have any useful pharmacologicalactivity.

Accordingly the present invention provides a compound of the formula(I): ##STR1## or a pharmaceutically acceptable salt thereof, wherein R¹is isopropyl or tertiary-butyl;

R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy or amino; and

R³ is hydrogen or methyl; for use as a β-blocker.

Suitably R¹ is an isopropyl group. Preferably R¹ is a tertiary-butylgroup.

R² is hydrogen, C₁₋₄ alkyl for example methyl or ethyl, C₁₋₄ alkoxy forexample methoxy or ethoxy, amino or hydroxy.

Suitably R² is hydrogen, amino or methyl. Preferably R² is hydrogen.

When R² is not hydrogen it is preferably in a meta- or para-position tothe pyridazinone ring.

Favourably the phenyl group is substituted in the 5- or 6-position ofthe pyridazinone ring, preferably in the 5-position.

Thus preferred compounds for use in this invention are those of theformula (II): ##STR2## and pharmaceutically acceptable salts thereofwherein R¹ is as hereinbefore defined.

Particular compounds for use in this invention are:

5-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]pyridazinone andpharmaceutically acceptable salts thereof,

5-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-3[2H]pyridazinone andpharmaceutically acceptable salts thereof,

6-[4-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinoneand pharmaceutically acceptable salts thereof,

6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone andpharmaceutically acceptable salts thereof,

4-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone andpharmaceutically acceptable salts thereof,

6-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-3[2H]-pyridazinone andpharmaceutically acceptable salts thereof,

6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3[2H]-pyridazinoneand pharmaceutically acceptable salts thereof, and

5-methyl-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinoneand pharmaceutically acceptable salts thereof.

The compounds for use in this invention have a chiral centre at the--CH(OH)-- moiety in the side chain. Suitably they are provided as aracemic mixture or a mixture of the R- and S-isomers in which theproportion of S-isomer is enhanced. Preferably the compounds for use inthis invention are provided as a racemic mixture or as the S-isomersubstantially free of the R-isomer, for example having less than 10%R-isomer, more suitably less than 5% and preferably less than 2%.

The compounds of the formulae (I) and (II) may form pharmaceuticallyacceptable acid addition salts with either organic or inorganic acids,for example those formed with hydrochloric, hydrobromic, hydriodic,methanesulphonic, sulphuric, maleic, fumaric, succinic, acetic,tartaric, citric and lactic acids.

In another aspect the present invention provides a pharmaceuticalcomposition which comprises a compound of the formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The compositions of this invention include those in a form adapted fororal, rectal, ocular or parenteral use, and may be used for thetreatment of humans and other mammals. Thus, the compounds of theformula (I) and pharmaceutically acceptable salts thereof may beadministered, for example, orally, rectally, ocularly or parentally.

In a preferred composition aspect of this invention a compound of theformula (I) or pharmaceutically acceptable salt thereof is in sterileform.

Suitably the compounds of the formula (I) and their pharmaceuticallyacceptable salts may be formulated as solutions, suspensions, syrups,capsules, lozenges, reconstitutable powders, tablets and sterile formssuitable for injection or infusion. These compositions may containconventional pharmaceutically acceptable materials such as diluents,binders, flavours, preservatives, disintegrants and colouring agents.Suitable examples of solid carriers include lactose, sucrose, talc,gelatin, agar, starch, magnesium stearate and acacia. Suitable examplesof liquid carriers include polyvinylpyrrolidine, lecithin,polyethyleneglycol, arachis oil, syrup, glycerine, water, ethanol,peanut oil and olive oil.

A typical suppository formulation comprises a compound of formula (I) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent forexample gelatin or cocoa-butter or other low melting vegetable waxes orfats.

Typical ophthalmic formulations comprise a compound of the formula (I)or a pharmaceutically acceptable salt thereof, which is active whenadministered in this way, in the form of an ointment, a solid forexample a solid insert suitably having a solid water-soluble polymer ascarrier, or a buffered isotonic liquid for example phosphate buffer,isotonic sodium borate, isotonic boric acid or isotonic sodium chloride.

Preferably the composition is in unit dosage form for example a tabletor capsule.

Each dosage unit contains preferably from about 10 to 500 mg of acompound of formula (I) or a pharmaceutically acceptable salt thereofcalculated as the free base, preferably from about 25 mg to about 250mg.

The invention also provides a method of producing β-adrenoceptorantagonist activity which comprises administering to a subject aneffective amount to produce said activity of a compound of the formula(I) or a pharmaceutically acceptable salt thereof.

The daily dosage regimen for an adult patient is from about 10 mg toabout 1500 mg of the compound of formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free base. The activeingredient may be administered from 1 to 6 times a day, sufficient toeffect β-adrenergic blockade. For ocular administration suitably 0.01 to30 mg of the compound of the formula (I) or pharmaceutically acceptablesalt thereof (calculated as the free base) is administered daily, in 1to 6 doses. Suitable concentrations for the active compound in thecarrier are 0.01 to 25% dependent on the nature of the carrier; typicalconcentrations for eye drop solutions are 0.25-0.5% suitably containing1-5 mg of active compound.

The compounds of the formula (I) are β-adrenoceptor antagonists and canbe used in the treatment of any disease that is conventionally treatedwith such drugs, for example angina, myocardial infarction,hypertension, arrhythmias, thyrotoxicosis, anxiety, migraine and tremor.The compounds of the formula (I) are also useful for treating glaucomaand lowering intraocular pressure. The β-adrenoceptor antagonistactivity of the compounds of the present invention may be demonstratedin a suitable test preparation such as cats anaesthetised withpentobarbitone sodium (Nembutal, Trade Mark), 60 mg/kg i.p. In suchanaesthetised cats, intravenous injections of isoprenaline causetachycardia, and vasodilatation in the hindlimb. These effects ofisoprenaline, which are dose-dependent and are due to stimulation ofβ-adrenoceptors, can be reduced or abolished by intravenousadministration of from about 0.01 to 100 micromoles/kg of theβ-adrenoceptor antagonist of the formula (I). The compounds of Examples1 to 7 were administered to anaesthetised cats and the doses (μmol/Kgintravenous) required to cause 50% reduction (ED₅₀) inisoprenaline-induced tachycardia (β₁) and 50% reduction inisoprenaline-induced vasodilatation (β₂) were recorded. The compounds ofthe Examples 2-7 gave ED₅₀ values in the range of 0.04 to about 0.5 (β₁)and 0.01 to 0.25 (β₂). The compound of Example 1 gave ED₅₀ values below0.01 for both β₁ and β₂ tests.

In a further aspect of this invention there are provided novel compoundswithin the formula (I) which are represented by the formula (III):##STR3## and pharmaceutically acceptable salts thereof wherein R¹ and R²are as hereinbefore defined with the proviso that when the pyridazinoneis 6-substituted the S-isomer is provided. Suitable and favourablesubstituents for the novel compounds of this invention are as previouslydescribed for the compounds for use as β-adrenoceptor antagonists. ByS-isomer we mean the S-isomer substantially free of the R-isomer, forexample having less than 10% R-isomer, more suitably less than 5% andpreferably less than 2%.

Thus particularly preferred compounds of this invention are:

5-[2-(3-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone andpharmaceutically acceptable salts thereof and

5-[2-(2-hydroxy-3-isopropylamino-propoxy)phenyl]-3[2H]-pyridazinone andpharmaceutically acceptable salts thereof.

In another aspect the present invention provides a process for thepreparation of a compound of the formula (III) or a pharmaceuticallyacceptable salt thereof, which process comprises:

(a) for 4- and 5-phenyl pyridazinones, the reaction of a compound of theformula (IV): ##STR4## wherein R² and R³ are as hereinbefore defined,with isopropylamine or tertiary butylamine; or

(b) the reaction of a compound of the formula (V): ##STR5## wherein R¹,R² and R³ are as hereinbefore defined, with a dehydrogenating agent; or

(c) the hydrolysis of a compound of the formula (VI): ##STR6## whereinR¹, R² and R³ are as hereinbefore defined, and Z is C₁₋₆ alkoxy,allyloxy, optionally substituted benzyloxy, or halo; or

(d) the resolution of a compound of the formula (III) when in racemicform to provide the S-isomer;

and if necessary forming a pharmaceutically acceptable salt.

The reaction of a compound of the formula (IV) and either isopropylamineor tertiary-butylamine is suitably conducted in a solvent at an elevatedtemperature, for example, in refluxing toluene.

Suitable dehydrogenating agents for reaction with a compound of theformula (V) include oxidative halogenating agents for example chloranilor sodium 3-nitrobenzenesulphonate. In addition N-bromosuccinimide issuitable for converting a compound of the formula (V) to a compound ofthe formula (I) when the phenyl ring is substituted at the 4- or5-position of the pyridazinone ring. The conditions for such reactionswill vary according to the reagent used, but will be conventional, forexample N-bromosuccinimide may be used in a solvent, for exampledimethylsulphoxide, at a non-extreme temperature, for example ambient.

Suitably in the compounds of the formula (VI) Z is C₁₋₆ alkoxy forexample methoxy or ethoxy. The dealkylation is conveniently performed byacidic hydrolysis. Alternatively Z suitably may be halo for examplechloro which is subjected to acidic hydrolysis.

Racemic mixtures of the compounds of the formula (III) may be resolvedby conventional methods.

During the processes of this invention the side chain may be protectedon the amino and/or hydroxy group if desired. For example the hydroxygroup may be acylated for example as CH₃ COO-- which may be removed bybasic hydrolysis.

Pharmaceutically acceptable salts of the compounds of the formula (III)may be prepared in conventional manner, for example acid addition saltsmay be prepared by treating the compounds of the formula (III) with theappropriate acid in a C₁₋₄ alkanol, or they may be prepared by the useof an ion-exchange resin to form the desired salt directly from the freebase or via a different acid addition salt.

The compounds of the formula (IV) may be formed by the reaction of basewith a compound of the formula (VII): ##STR7## wherein R² and R³ are ashereinbefore defined, and one of X and Y is halo for example bromo andthe other is hydroxy. Suitably the base is t-butylamine orisopropylamine, in which case the compound of the formula (IV) issuitably an unisolated intermediate in the preparation of a compound ofthe formula (III).

The compounds of the formula (VII) may be conveniently prepared by thereaction of a compound of the formula (VIII): ##STR8## wherein R² and R³are as hereinbefore defined, with an oxidative halogenating agent, forexample N-bromosuccinimide.

The compounds of the formula (VIII) may be prepared by thedehydrogenation of a compound of the formula (IX): ##STR9## wherein R²and R³ are as hereinbefore described, in a manner analogous to thatdescribed for dehydrogenation previously.

In a particularly convenient aspect a compound of the formula (IX) maybe reacted with an oxidative halogenating agent, for exampleN-bromosuccinimide, to provide the compound of the formula (VII) withoutisolation of the intermediate.

Alternatively the compound of the formula (IV) may be prepared by thealkylation of a compound of the formula (X): ##STR10## wherein R² and R³are as hereinbefore defined, with an alkylating agent, for exampleepichlorohydrin or epibromohydrin.

The compounds of the formula (X) may be prepared by the dehydrogenationof a compound of the formula (XI): ##STR11## wherein R² and R³ are ashereinbefore defined, in a manner analogous to that described fordehydrogenation previously.

The compounds of the formulae (V) and (VI) may be prepared byelaborating an hydroxy group to R¹ NHCH₂ CH(OH)CH₂ O-- by the samegeneral manner as hereinbefore described. Thus compounds of the formulae(IX) and (V) may be prepared from compounds of the formula (XI) andcompounds of the formula (VI) may be prepared from the compounds of theformula (XII): ##STR12## wherein R², R³ and Z are as hereinbeforedefined.

The compounds of the formulae (XI) and (XII) and also compounds of theformulae (IV)-(X), wherein the phenyl ring is substituted at the6-position of the pyridazinone ring, may be prepared for example bymethods described in the U.S. Pat. Nos. 3,931,177 and 4,053,601.

Compounds of the formulae (IX), (X) and (XI) wherein the phenyl ring issubstituted at the 4- or 5-position of the pyridazinone ring may beprepared in the same general manner as for the 6-substituted compounds.For example by reacting with hydrazine an appropriately substituted 2or3-phenyl ω-carboxypropionaldehyde wherein the aldehyde and acidfunctions are "masked" if necessary, for example the aldehyde functionmay be in the form of an acetal or the aldehyde and acid functions maybe joined to form a hydroxy- or alkoxy-lactone, to form adihydropyridazinone ring. The β-blocking side chain then may beelaborated and dehydrogenated as necessary. In addition5-phenyldihydropyridazinones may be prepared by reacting a4-phenylfuran-2-one with hydrazine. See also, for example, the methodsof Bourguignon and Wermuth, J. Org. Chem. 1981, 4889-4894 for thepreparation of 5-phenylpyridazinones.

Furthermore compounds of the formula (XII) wherein the phenyl ring issubstituted at the 4-position of the pyridazinone ring, may be preparedby known methods. For example compounds wherein Z is chloro may beprepared by reaction of phosphorus oxychloride with a correspondingcompound of the formula (X) wherein the hydroxy group is protected. Suchcompounds of the formula (X) may be prepared by a Grignard reaction with4-chloropyridazinone and a protected hydroxyphenyl magnesium bromide.Compounds of the formula (XII) wherein Z is alkoxy may be prepared bythe methods of Example 3 with appropriate protection of the R²substituent if necessary.

As previously stated racemic mixtures of the compounds of the formula(III) may be resolved by conventional methods. Alternatively anyresolution may be performed on intermediates as described hereinbeforeat any convenient stage of the synthesis.

The following Examples serve to illustrate the invention.

EXAMPLE 15-[2-(3-t-Butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinonehydrochloride

(i) 4-(2-Allyloxyphenyl)-5-ethoxydihydro-2-furanone

Potassium hydroxide (8.5 g) in methanol (60 ml) was added to a solutionof ethyl coumarin-3-carboxylate (10 g) in methanol (100 ml) and themixture was refluxed for 90 minutes, whereupon a precipitate formed.Allyl bromide (18 ml) in methanol (20 ml) was added, the precipitatedissolved, the mixture was refluxed for a further two hours whereuponanother precipitate formed. The mixture was poured into water andextracted into diethyl ether. The ether extracts were washed withaqueous sodium hydroxide, water, dried over MgSO₄ and then evaporatedunder reduced pressure to give as an oil a mixture of allyl and methylesters of 2-allyloxybenzylidenemalonic acid (7 g). This was combinedwith material obtained from a larger scale reaction.

A solution of the foregoing esters (23 g) in tetrahydrofuran (25 ml) wasadded to methyl methylsulphinylmethylsulphide (8.5 ml) and butyl lithium(6 g) in tetrahydrofuran (100 ml) and hexane (60 ml) at -70° C. Theresultant solution was warmed to room temperature, poured into aqueousammonium chloride, extracted into diethyl ether and evaporated underreduced pressure to afford slightly impure ethyl3-(2-allyloxyphenyl)-2-ethoxycarbonyl-4-methylsulphinyl-4-methylthiobutanoate(30.2 g) as a yellow oil. This material was dissolved in a mixture oftriethyl orthoformate (18 ml), sulphuric acid (1 ml) and anhydrousethanol (90 ml). After three days the solution was poured into aqueoussodium bicarbonate, extracted into diethyl ether and evaporated underreduced pressure to afford ethyl3(2-allyloxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutanoate as a brownoil. A solution of this material (26 g) and potassium hydroxide (14 g)in ethanol (140 ml) was refluxed for four hours, poured into water andacidified with concentrated hydrochloric acid to yield, on extractioninto diethyl ether and evaporation under reduced pressure,3-(2-allyloxyphenyl)-2-carboxy-4,4-diethoxybutanoic acid (15.5 g) as abrown oil. This acid (15 g) was distilled (Hg diffusion pump) to give4-(2-allyloxyphenyl)-5-ethoxydihydro-2-furanone (10.6 g) as a yellowoil, boiling point 200° C. (bath temperature)/less than 0.01 mm Hg.

(ii) 5-(2-Allyloxyphenyl)-4,5-dihydro-3[2H)-pyridazinone

Hydrazine hydrate (2.8 ml) was added to a solution of4-(2-allyloxyphenyl)-5-ethoxydihydro-2-furanone (9.8 g) in acetic acid(30 ml) and water (27 ml). The solution was refluxed for 90 minutes,poured into aqueous sodium bicarbonate, extracted into diethyl ether,evaporated under reduced pressure and the resultant solid recrystallisedfrom benzene to afford5-(2-allyloxyphenyl)-4,5-dihydro-3[2H]-pyridazinone (6.5 g) as whitecrystals, m.p. 93°-95° C.

(iii) 5-[2-(3-t-Butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinonehydrochloride

N-Bromosuccinimide (2.2 g) was added to a solution of5-(2-allyloxyphenyl)-4,5-dihydro-3[2H]-pyridazinone (1.4 g) and water(0.5 ml) in dimethylsulphoxide (20 ml). After three hours the solutionwas diluted with ethyl acetate, washed with water, dried and evaporatedunder reduced pressure to yield an oil (2.2 g). This oil was dissolvedin t-butylamine (20 ml) and toluene (90 ml) and the solution refluxedfor three days. The mixture was poured into dilute sulphuric acid,washed with ether, basified with aqueous sodium hydroxide, extractedinto ethyl acetate and evaporated under reduced pressure to afford5-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3-[2H]-pyridazinone (1.3g) as an oil.

This was dissolved in 0.1M hydrochloric acid (38 ml), washed with etherand the water removed under reduced pressure to give a solid (1.5 g)which was recrystallised from ethanol-water to give the title compound(1.3 g) as white crystals, m.p. 265°-267° C. (decomp).

The title compound (25 mg), sucrose (40 mg), starch (15 mg), talc (3 mg)and stearic acid (1 mg) are screened, mixed and filled into a hardgelatin capsule.

EXAMPLE 26-[4-Amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone

(i) 4-Acetamido-2-hydroxyacetophenone (50 g), anhydrous potassiumcarbonate (53.8.g) and allyl bromide (24.63 ml) were vigorously stirredand refluxed in anhydrous acetone (200 ml) for 19 hours. Further allylbromide (25 ml) and potassium carbonate (17.9 g) were added and thestirred mixture heated for another 3 hours. The reaction mixture wasfiltered and evaporated to afford a solid which on trituration underdiethyl ether gave 4-acetamido-2-allyloxyacetophenone (50.77 g), m.p.108°-110° C.

(ii) A stirred melt of 4-acetamido-2-allyloxyacetophenone (34.95 g) andglyoxylic acid hydrate (13.44 g) was heated at oil bath temperature(105°-110° C.) for 2 hours. The reaction mixture was cooled to 60° C.,treated with water (60 ml) and concentrated aqueous ammonia (12 ml) andwashed with dichloromethane.

The ammoniacal solution was refluxed for 2 hours with hydrazine hydrate(7.5 ml) to afford 6-(4-acetamido-2-allyloxy)-3[2H]-pyridazinone (23 g)which on recrystallisation from ethanol gave a m.p. of 204°-5° C.

(iii) N-Bromosuccinimide (8.74 g) was added in portions over 20 minutesto a stirred solution of 6-(4-acetamido-2-allyloxy)-3[2H]-pyridazinone(22 g) in anhydrous dimethyl sulphoxide (49 ml) and water (2.45 ml) at atemperature of 10°-15° C. The solution was stirred for 30 minutes atroom temperature and diluted with water (200 ml). The crude productswere collected, washed with water and dissolved in methanol (70 ml).t-Butylamine (70 ml) was added to this solution and the mixture wasrefluxed for 16 hours, evaporated under reduced pressure and the residuewas heated on a steam bath for one hour with 2N sodium hydroxidesolution. The pH was adjusted to 7 with hydrochloric acid and then to 10with potassium carbonate to give a crude mixture of6-[4-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinoneand 5-bromo analogue thereof. This mixture was dissolved in aqueoussodium hydroxide and hydrogenated at 350 kPa (50 p.s.i.) over 10% Pd/Ccatalyst. The catalyst was filtered off, and the filtrate adjusted topH7 and then to about pH10 to give the title compound which wascrystallised from acetone to give m.p. 198.5°-201.5° C.

The title compound (25 mg), sucrose (40 mg), starch (15 mg), talc (3 mg)and stearic acid (1 mg) are screened, mixed and filled into a hardgelatin capsule.

EXAMPLE 34-[2-(3-t-Butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone

(i) Phenyl magnesium bromide (prepared from bromobenzene (171 g),magnesium (38.8 g) and diethyl ether (1.6 l)) was slowly added to astirred solution of 4,5-dichloro-3[2H]-pyridazinone (60 g) intetrahydrofuran (1 l) cooled at water bath temperature. This mixture wasstirred at room temperature for 30 minutes and hydrolysed with 20%ammonium chloride solution (800 ml) in the cold. The aqueous layer wasextracted with diethyl ether and the combined organic extracts werewashed with dilute hydrochloric acid, water, brine, dried (MgSO₄) andevaporated under reduced pressure to give5-chloro-4-phenyl-3[2H]-pyridazinone (55.13 g), m.p. 193°-5° C. onrecrystallisation from ethyl acetate.

(ii) The above product (45 g), sodium hydroxide (21.8 g), water (600ml), dimethylformamide (60 ml) and 10% Palladium of charcoal (1.5 g)were shaken under hydrogen (350 kPa;50 p.s.i.) until hydrogen uptake wascomplete. Sodium hydroxide solution was added to dissolve a precipitateand the filtered solution was neutralised to afford4-phenyl-3[2H]-pyridazinone (35.7 g), m.p. 216.5°-219° C. onrecrystallisation from ethanol.

(iii) Powdered 4-phenyl-3[2H]-pyridazinone (32.7) was added over aperiod of 60 minutes to a stirred mixture of fuming nitric acid (66.6ml) and concentrated sulphuric acid (6.6 ml) at -10° C. The mixture wasstirred at -10° C. for a further 10 minutes and at 0° C. for a further30 minutes before being poured into ice-water (900 ml) to give a paleyellow mixture of the three isomers of 4-nitrophenyl-3[2H]-pyridazinone(40.65 g), i.e. the 4-(2-nitrophenyl)-, 4-(3-nitrophenyl)- and4-(4-nitrophenyl)- derivatives.

(iv) The pyridazinones so obtained (20 g), sodium hydroxide (7.73 g),water (600 ml), dimethylformamide (67 ml) and 10% Palladium on charcoal(1 g) were shaken under hydrogen (205 kPa;30 p.s.i.) until the uptake ofhydrogen was complete. This process was repeated on a further amount ofthe pyridazinone mixture (58.6 g) in batches. Acidification to pH 5-6 ofthe filtered solutions gave a mixture of4-(aminophenyl)-3[2H]-pyridazinones (34.46 g). A further quantity ofthis material (24.41 g) was obtained from the filtrate.

The unpurified product was stirred for 10 minutes with dilutehydrochloric acid (1000 ml), filtered, and evaporated under reducedpressure to afford a residue which was either acetylated as thehydrochloride in water with sodium acetate and acetic anhydride or asthe free base with acetic anhydride-pyridine. The resultant mixture ofacetamido compounds was digested with chloroform containing methanol togive an impure extract which was purified by column chromatography(silica gel, chloroform-methanol) to give4-(2-acetamidophenyl)-3[2H]-pyridazinone m.p. 235°-6° C.

Hydrolysis of this material with 18% hydrochloric acid with subsequentevaporation, dissolution in 2N sodium hydroxide and acidification to pH5-6 afforded 4-(2-aminophenyl)-3[2H]-pyridazinone m.p. 234.5°-236.5° C.

To a stirred mixture of 4-(2-aminophenyl)-3[2H]-pyridazinone (10.64 g),sulphuric acid (7.7 ml) and water (65 ml) at 0 to 5° C. was addeddropwise over 20 minutes sodium nitrite (4.16 g) in water (15 ml). After30 minutes at 5° C, boric acid (5.3 g) and sulphuric acid (7.7 ml) wereadded, the mixture was warmed to room temperature and subsequently to70° C. On standing for 18 hours a solid (5.4 g) precipitated. This solidwas dissolved in warm water (100 ml) and taken to pH 8 with potassiumcarbonate to yield a solid (3.32 g). Neutralisation of the acidicreaction mixture yielded further solid (5.32 g). Recrystallisation fromcyclohexane of these solids afforded benzofuro[2,3-c]-pyridazine m.p.120°-122° C.

(v) To a stirred solution of benzofuro[2,3-c]-pyridazine (5.09 g) indimethylformamide (40 ml) containing a suspension of sodium hydride(1.68 g, 50% oil) was added dry methanol (1.5 ml). The mixture washeated to 70° C. for 30 minutes and treated with epibromohydrin (10.2ml) and stirring was continued at room temperature for 150 minutes. Themixture was poured into water (300 ml), taken to pH 10 with sodiumhydroxide, extracted into dichloromethane and the organic extract wasevaporated under reduced pressure to afford an oil that was purified bycolumn chromatography (silica, chloroform-petrol, chloroform,chloroform-methanol) to afford4-[2-(2,3-epoxypropoxy)phenyl]-3-methoxypyridazine as an oil. This washeated under reflux for 60 minutes with t-butylamine (20 ml) in methanol(50 ml) and the mixture was allowed to stand overnight. Evaporationunder reduced pressure afford an oil which on treatment with diethylether-petrol gave4-(2-[3-t-butylamino-2-hydroxypropoxy)phenyl]-3-methoxypyridazine, m.p.109.5°-110.5° C. from cyclohexane.

(vi) The above compound (1.37 g) and 18% hydrochloric acid (82 ml) wereheated under reflux for 4 hours. Evaporation under reduced pressure gavea solid which on trituration with diethyl ether afforded4-(2-[3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinonehydrochloride as a quarter hydrate, m.p. 240°-242° C.

The title compound (25 mg), sucrose (40 mg), starch (15 mg), talc (3 mg)and stearic acid (1 mg) are screened, mixed and filled into a hardgelatin capsule.

EXAMPLE 46-[2-(3-t-Butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone

A stirred solution of3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl-6-chloropyridazine (10.0 g,0.03 mol) in 18% hydrochloric acid (60 ml) was heated under reflux for 8hours. Potassium carbonate was added to the cold solution to take it topH 10, and after allowing the mixture to stand for 2 hours the solid wascollected by filtration and washed with water to give a crude hydrate(10.35 g). Recrystallisation from ethyl acetate gave6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone (7.42g) as a colourless solid, m.p. 161.5°-163.5° C.

The title compound (25 mg), sucrose (40 mg), starch (15 mg), talc (3 mg)and stearic acid (1 mg) are screened, mixed and filled into a hardgelatin capsule.

EXAMPLE 56-[2-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-3[2H]-pyridazinone

A solution of6-[2-(2-acetoxy-3-N-acetylisopropylaminopropoxy)phenyl]-3[2H)-pyridazinone(3 g) in methanol (75 ml) was heated under reflux with sodium hydroxide(1.58 g) in water (24 ml) for 2 hours. The residue after evaporation wasdissolved in water (20 ml) and acetic acid was added dropwise toprecipitate the crude product which was recrystallised fromethanol-ether to afford the title compound, m.p. 150.5°-152.5° C.Treatment with ethanolic HCl and crystallisation from ethanol-ether gaveas a solid the hydrochloride, m.p. 203°-204° C.

The title compound (25 mg), sucrose (40 mg), starch (15 mg), talc (3 mg)and stearic acid (1 mg) are screened, mixed and filled into a hardgelatin capsule.

EXAMPLE 66-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3[2H]-pyridazinone

6-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-methoxypyridazinewas hydrolysed with hydrochloric acid in a manner similar to thatdescribed in Example 3 vi). Addition of an excess of potassium carbonateto the cooled solution afforded the title compound which wasrecrystallised from ethanol/ether, m.p. 159°-161° C.

The starting-materials for Examples 4, 5 and 6 are preparable by themethods of U.S. Pat. No. 4,053,601.

The title compound (25 mg), sucrose (40 mg), starch (15 mg), talc (3 mg)and stearic acid (1 mg) are screened, mixed and filled into a hardgelatin capsule.

EXAMPLE 75-Methyl-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone

5-Methyl-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3[2H]-pyridazinone(preparable from British Patent Specification No. 1488330) (1.3 g) andsodium 3-nitrobenzene sulphonate (0.88 g) were mixed in aqueous sodiumhydroxide (0.38 g in 50 ml) and stirred under reflux for 3 hours. Thereaction mixture was cooled, neutralised with hydrochloric acid andevaporated under reduced pressure to afford a residue. This wasdissolved in water, on standing a solid precipitated which was filteredoff (recovered sodium 3-nitrobenzene sulphonate). The filtrate wasshaken with chloroform whereupon a white solid precipitated which wascollected and dried to afford the title compound (0.4 g).

This was dissolved in dilute hydrochloric acid and the solution wasevaporated to dryness. The residue was recrystallised from ethanol/etherto give as a white solid5-methyl-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinonehydrochloride (0.3 g), m.p. 293°-295° C.

The title compound (25 mg), sucrose (40 mg), starch (15 mg), talc (3 mg)and stearic acid (1 mg) are screened, mixed and filled into a hardgelatin capsule.

EXAMPLE 8

Replacing tertiary-butylamine in Example 1 with isopropylamine gives5-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-3[2H]-pyridazinone.

EXAMPLE 9

5-(2-Allyloxy-4-methylphenyl)-4,5-dihydro-3[2H]-pyridazinone is reactedwith N-bromosuccinimide and subsequently with tertiary-butylamine in amanner similar to that of Example 1 to give5-[(2-(3-t-butylamino-2-hydroxypropoxy)-4-methyl)phenyl]-3[2H]-pyridazinone.

EXAMPLE 105-[2-(3-t-Butylamino-2-hydroxypropoxy)phenyl]-6-methylpyridazinonehydrochloride

(i) A solution of the mixture of allyl and methyl esters of2-allyloxybenzylidenemalonic acid (described in Example 1(i)) intetrahydrofuran is treated with 1-methylsulphinyl-1-methylthioethane andbutyl lithium in hexane at -70° C. to give ethyl3-(2-allyloxyphenyl)-2-ethoxycarbonyl-4-methyl-4-methylsulphinyl-4-methylthiobutanoatewhich is subsequently reacted in a manner similar to that described inExample 1(i) to give4-(2-allyloxyphenyl)-5-ethoxy-5-methyl-2-oxotetrahydrofuran.

(ii) The above tetrahydrofuran is transformed by a sequence of reactionssimilar to those described in Example 1(ii) and (iii) to give the titlecompound as a hydrochloride salt.

EXAMPLE 115-[2-(3-t-Butylamino-2-hydroxypropoxy)phenyl]-4-methylpyridazinonehydrochloride

(i) A solution of ethyl3-(2-allyloxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutanoate (describedin Example 1(i)), in ether is treated with sodium ethoxide andsubsequently with methyl iodide to give ethyl3-(2-allyloxyphenyl)-4,4-diethoxy-2-ethoxycarbonyl-2-methylbutanoate,which is subsequently reacted in a manner similar to that described inExample 1(i) to give4-(2-allyloxyphenyl)-5-ethoxy-3-methyl-2-oxotetrahydrofuran.

(ii) The above tetrahydrofuran is transformed by a sequence of reactionssimilar to those described in Example 1 (ii) and (iii) to give the titlecompound as a hydrochloride salt.

What is claimed is:
 1. A pharmaceutical composition in dosage unit formhaving β-adrenoceptor antagonist activity comprising an effective amountto produce said activity of a compound of formula (I): ##STR13## or apharmaceutically acceptable salt thereof, wherein the substituted phenylis attached at the 5-position of the 3[2H]-pyridazinone;R¹ is isopropylor tertiary-butyl; R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy oramino;and R³ is hydrogen or methyl; and a pharmaceutically acceptablecarrier.
 2. A pharmaceutical composition according to claim 1 wherein R¹is a tertiary-butyl group.
 3. A pharmaceutical composition according toclaim 1 wherein R² is hydrogen or methyl.
 4. A pharmaceuticalcomposition according to claim 1 wherein R³ is hydrogen.
 5. Apharmaceutical composition according to claim 1 which comprises5-[2-(3-butylamino-2-hydroxypropoxy)phenyl]-3[2H]-pyridazinone or apharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition according to claim 1 which comprises5-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-3[2H]-pyridazinone or apharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition according to claim 1 which comprises5-[2-(3-t-butylamino-2-hydroxypropoxy)-phenyl]-3-[2H]-pyridazinonehydrochloride.
 8. A pharmaceutical composition according to claim 1 in aform for oral administration.
 9. A pharmaceutically compositionaccording to claim 1 in a form for ocular administration.
 10. Apharmaceutical composition according to claim 1 wherein the compound andcarrier are sterile.
 11. A method of producing β-adrenoceptor antagonistactivity which comprises administering to a mammal an effective amountto produce said activity of a compound of the formula (I): ##STR14## ora pharmaceutically acceptable salt thereof, wherein the substitutedphenyl is attached to the 5-position of the 3[2H] pyridazinone;R¹ isisopropyl or tertiary-butyl; R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy or amino; and R³ is hydrogen or methyl.